Therapeutic blockade of activin-A improves NK cell function and antitumor immunity

Sarcomas are heterogeneous malignant mesenchymal neoplasms with limited sensitivity to immunotherapy. We recently demonstrated an increase in Kynurenine Pathway (KP) activity in the plasma of sarcoma patients treated with pembrolizumab. While the KP has already been described to favor immune escape through the degradation of L-Tryptophan and production of metabolites including L-Kynurenine, Indoleamine 2,3 dioxygenase (IDO1), a first rate-limiting enzyme of the KP, still represents an attractive therapeutic target, and its blockade had not yet been investigated in sarcomas. Using immunohistochemistry, IDO1 and CD8, expression profiles were addressed within 203 cases of human sarcomas. At a preclinical level, we investigated the modulation of the KP upon PDL1 blockade in a syngeneic model of sarcoma through mRNA quantification of key KP enzymes within the tumor. Furthermore, in order to evaluate the possible anti-tumor effect of IDO blockade in combination with PDL1 blockade, an innovative IDO inhibitor (GDC-0919) was used. Its effect was first assessed on Kynurenine to Tryptophan ratio at plasmatic level and also within the tumor. Following GDC-0919 treatment, alone or in combination with anti-PDL1 antibody, tumor growth, immune cell infiltration, and gene expression profiling were measured. IDO1 expression was observed in 39.1% of human sarcoma cases and was significantly higher in tumors with high CD8 infiltration. In the pre-clinical setting, blockade of PDL1 led to a strong anti-tumor effect and was associated with an intratumoral inflammatory cytokines signature driven by Ifng but also with a modulation of the KP enzymes including Ido1 and Ido2. IDO1 inhibition using GDC-0919 resulted in (i) a significant decrease of plasmatic Kynurenine to Tryptophan ratio and in (ii) a decrease of tumoral Kynurenine. However, GDC-0919 used alone or combined with anti-PDL1, did not show anti-tumoral activity and did not affect the tumor immune cell infiltrate. In order to elucidate the mechanism(s) underlying the lack of effect of GDC-0919, we analyzed the gene expression profile of intratumoral biopsies. Interestingly, we have found that GDC-0919 induced a downregulation of the expression of pvr and granzymes, and an upregulation of inhba and Dtx4 suggesting a potential role of the IDO pathway in the control of NK function.

Section: Discussionmentioning

confidence: 99%

IDO Targeting in Sarcoma: Biological and Clinical Implications

Nafia¹,

Toulmonde

Bortolotto³

et al. 2020

“…As technology has advanced, larger numbers of proteins have been identified in an unbiased manner, demonstrating the growing utility of proteomics (276,277). A more recent study used proteomic analysis to identify proteins important for NK cell proliferation and pointed a pathway toward increasing the activity of NK cells in a tumor model through therapeutic blockade (278).…”

Section: Omics Studies On Nk Cell Activationmentioning

confidence: 99%

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

Murin

2020

It has been well-established that antibody isotype, glycosylation, and epitope all play roles in the process of antibody dependent cellular cytotoxicity (ADCC). For natural killer (NK) cells, these phenotypes are linked to cellular activation through interaction with the IgG receptor FcγRIIIa, a single pass transmembrane receptor that participates in cytoplasmic signaling complexes. Therefore, it has been hypothesized that there may be underlying spatial and geometric principles that guide proper assembly of an activation complex within the NK cell immune synapse. Further, synergy of antibody phenotypic properties as well as allosteric changes upon antigen binding may also play an as-of-yet unknown role in ADCC. Understanding these facets, however, remains hampered by difficulties associated with studying immune synapse dynamics using classical approaches. In this review, I will discuss relevant NK cell biology related to ADCC, including the structural biology of Fc gamma receptors, and how the dynamics of the NK cell immune synapse are being studied using innovative microscopy techniques. I will provide examples from the literature demonstrating the effects of spatial and geometric constraints on the T cell receptor complex and how this relates to intracellular signaling and the molecular nature of lymphocyte activation complexes, including those of NK cells. Finally, I will examine how the integration of high-throughput and "omics" technologies will influence basic NK cell biology research moving forward. Overall, the goal of this review is to lay a basis for understanding the development of drugs and therapeutic antibodies aimed at augmenting appropriate NK cell ADCC activity in patients being treated for a wide range of illnesses.

“…Although ILC1 are tissue resident and unlikely to migrate to other tissues (7)(8)(9), their function in cancer is poorly understood. Recent studies have revealed that transforming growth factor-beta (TGF-β) signaling (either by TGF-β itself or indirectly by Activin-A) can suppress cellular metabolism and effector functions (10)(11)(12). This suppressive signaling drives the upregulation of ILC1-related markers in circulating mouse or human NK cells, suggesting the possibility of intercellular plasticity which could be important within the tumor microenvironment (TME) (11,13,14).…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have revealed that transforming growth factor-beta (TGF-β) signaling (either by TGF-β itself or indirectly by Activin-A) can suppress cellular metabolism and effector functions (10)(11)(12). This suppressive signaling drives the upregulation of ILC1-related markers in circulating mouse or human NK cells, suggesting the possibility of intercellular plasticity which could be important within the tumor microenvironment (TME) (11,13,14). NK cell cytotoxicity can be controlled by many stimulatory (NKp30, NKp44, NKp46, CD16) and inhibitory (PD1, TIM3, TIGIT, KLRG1) surface receptors (15).…”

Section: Introductionmentioning

confidence: 99%

Tumor Microenvironment-Associated Extracellular Matrix Components Regulate NK Cell Function

Rossi

Trindade

Souza-Fonseca-Guimarães

2020

Self Cite

The tumor microenvironment (TME) is composed of multiple infiltrating host cells (e.g., endothelial cells, fibroblasts, lymphocytes, and myeloid cells), extracellular matrix, and various secreted or cell membrane-presented molecules. Group 1 innate lymphoid cells (ILCs), which includes natural killer (NK) cells and ILC1, contribute to protecting the host against cancer and infection. Both subsets are able to quickly produce cytokines such as interferon gamma (IFN-γ), chemokines, and other growth factors in response to activating signals. However, the TME provides many molecules that can prevent the potential effector function of these cells, thereby protecting the tumor. For example, TME-derived tumor growth factor (TGF)-β and associated members of the superfamily downregulate NK cell cytotoxicity, cytokine secretion, metabolism, proliferation, and induce effector NK cells to upregulate ILC1-like characteristics. In concert, a family of carbohydrate-binding proteins called galectins, which can be produced by different cells composing the TME, can downregulate NK cell function. Matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase (ADAM) are also enzymes that can remodel the extracellular matrix and shred receptors from the tumor cell surface, impairing the activation of NK cells and leading to less effective effector functions. Gaining a better understanding of the characteristics of the TME and its associated factors, such as infiltrating cells and extracellular matrix, could lead to tailoring of new personalized immunotherapy approaches. This review provides an overview of our current knowledge on the impact of the TME and extracellular matrix-associated components on differentiation, impairment, and function of NK cells.